The proteolysis of the type 1 membrane-anchored amyloid precursor protein (APP) by the sequential actions of β- and γ-secretases results in amyloid-β (Aβ) peptide production that is thought to be causal for Alzheimer's disease (AD), cerebral amyloid angiopathy (CAA), certain forms of HIV associated neurocognitive impairment (HAND), certain forms of Lewy body dementia, inclusion body myositis, and certain forms of mild cognitive impairment (MCI) (Selkoe, 1999; Sinha et al., 1999; Games et al., 1995; Higgins et al., 1995). Inhibition or modulation of β- and/or γ-secretases constitutes important therapeutic strategies for AD and has become the centerpiece of therapeutically oriented research on this disease.
Presenilin 1 and 2 (PS1 and PS2), two integral membrane proteins found in the endoplasmic reticulum and Golgi apparatus, are the major enzymatic targets for γ-secretase inhibition for the treatment of AD (Seiffert et al., 2000). However, apart from their roles in AD, PS1 and PS2 also control the Notch signaling pathway responsible for cell proliferation and differentiation during embryonic development (Wolfe et al., 1999). PS1/2 knockout mice have massive neuronal loss, skeletal defects, underdeveloped subventricular areas and severe hemorrhages, and only a few types of PS1/2 knockout mouse models could survive after birth (Shen et al., 1997; Wong et al., 1997; Haass et al., 1999; Ester et al., 2000). Other substrates of PS1/2 have also been identified, suggesting pleotropic function of the PSs (Haass, 2004). Most importantly, recent clinical trials have indicated that the inhibition of γ-secretase is likely to cause undesirable side effects (Coric et al., 2012). Indeed, several such inhibitors, including avagacestat (Bristol-Myers Squibb), tarenflurbil (Flurizan, Myriad Genetics), and semagacestat (Eli Lilly and Co.), have failed to complete Phase 3 clinical trials (Cork et al., 2012; Green et al., 2009; Doody et al., 2013; Schor, 2011; Gupta, 2013). In the case of semagacestat, activities of daily living and cognition even worsened in treated patients (Doody et al., 2013; Schor, 2011; Gupta, 2013).
Like γ-secretase, β-secretase, widely known as β-site amyloid precursor protein cleaving enzyme 1 (BACE1), has also been identified as a prime therapeutic target for AD intervention. Its inhibition would halt the formation of Aβ at the first step of APP amyloidogenic processing. The therapeutic potential of BACE1 has been confirmed, e.g. genetic inhibition of the enzyme rescues memory deficits in AD model animals, (Ohno et al., 2004) and BACE1-deficient neurons fail to secrete Aβ peptides or generate β-C terminal fragment (β-CTF) (Cai et al., 2001). In view of these strong in vivo and in vitro validations of critical roles of BACE1 in Aβ generation and AD pathology, intense efforts are underway in both academia and industry to develop potent inhibitors of BACE1. Most of the early BACE1 inhibitors were non-cleavable peptide-based transition state analogues modeled after the β-secretase cleavage site of APP (Hong et al., 2000).
Unfortunately, while these peptidomimetic BACE1 inhibitors show dramatic impacts on Aβ generation in vitro, the majority of these inhibitors tend to possess poor drug-like properties in vivo, due to poor oral bioavailability, short serum half-life, or low blood-brain barrier (BBB) penetration. More recently, a number of non-peptidomimetic candidates for BACE1 inhibitors have been developed, including carbinamincs, acylguanidines, aminoquinazolines, and aminothiazines (Zhu et al., 2010; Wyss et al., 2012; Ghosh et al., 2014; Oehlrich et al., 2014). The less BBB penetration has also been solved with the development of potent third-generation small-molecule BACE1 inhibitors that exhibit satisfactory pharmacokinctics profiles and robust cerebral Aβ reduction in preclinical tests (Evin et al., 2011; Probst et al., 2012). As a result, several BACE1 inhibitors have entered clinical trials, including MK8931 (Merck), LY2886721 (Eli Lilly and Co.) and E2609 (Eisai) (Yan et al., 2014).